Acute and chronic hyperglycemia impair learning and memory; however the biological mechanisms underlying these deficits are poorly understood. Our objective is to characterize how glucose affects neurochemical function in order to understand the memory- impairing effects of hyperglycemia. This project tests two hypotheses: 1) acute central hyperglycemia impairs memory by enhancing GABA activity in the medial septum, which in turn 2) decreases hippocampal acetylcholine (ACh) function. Using in vivo microdialysis, intra-cerebral drug injections, and behavioral assays in rats, the specific aims of this proposal are 1) to determine whether hyperglycemia affects septal extracellular GABA levels, 2) to determine whether the effects of hyperglycemia on septal GABA levels are activity-dependent, 3) to determine whether hyperglycemia-induced increases in septal GABA levels impair memory, 4) to determine whether increases in GABA are derived from neuronal sources and to determine whether glucose-induced memory deficits and glucose-induced increases in GABA levels involve hyperosmolarity and glycolysis, 5) to determine whether the memory-impairing effects of septal hyperglycemia involve an inhibitory effect on extracellular ACh levels in the hippocampus, and 6) to determine whether the memory-impairing effects of septal hyperglycemia are reversed by increasing hippocampal extracellular ACh levels. The effects of acute increases in glucose levels are relevant to diabetes; most diabetic patients are treated with insulin or oral hypoglycemic drugs and are therefore more likely to suffer from acute episodes of hyperglycemia. Memory impairments are more common in diabetic patients than in the general population; in many cases these deficits are related to degree of hyperglycemia. Diabetic patients have poorer recall of medication recommendations than do non-diabetic patients, which may interfere with their ability to comply with medical regimens and control glycemic levels. Understanding the neurochemical mechanisms that contribute to hyperglycemia-related memory losses could lead to the development of treatments that attenuate cognitive deficits and improve quality of life in diabetic patients.